The human brain and spinal cord are covered with meningeal membranes whose integrity is critical to the operation of the central nervous system. When the integrity of a person's meningeal membranes is intentionally or accidentally compromised, serious consequences may ensue, unless the membranes can be repaired.
The meningeal membrane comprises three overlapping layers of tissue, which are in order from outside to inside, the dura mater (or dura), the arachnoid and the pia mater. Repairing damaged meningeal membranes has largely focused on implantable and/or resorbable constructs (known as dural substitutes) which are grafted over the damaged dura mater and are designed to replace and/or regenerate the damaged tissue. Researchers have experimented with a wide variety of substances as dural substitutes, but have not found a dural substitute that is safe, effective and mass-marketable.
Autologous grafts of tissue from other parts of the body, such as fascia lata and pericardium, can be effective as dural substitutes; however, autologous tissue is relatively difficult to obtain and can require the additional costs and risks of a second operation for the patient. By definition, such tissues cannot be mass-marketed.
Cadaverous dura mater has also been employed as a dural substitute. Like autologous tissues, cadaverous tissues can be difficult to obtain, and thus cannot be mass-marketed. Only about 4 to 5 transplantable units can be prepared from each donor, and cultural biases make it difficult to readily obtain donors.
More importantly, cadaverous dural substitutes have been implicated in the transmission of prion infections. An Oct. 6, 1997 meeting of the U.S. Food and Drug Administration (FDA) relating to such dural substitutes resulted in a call for stricter processing controls, and a warning that such dural substitutes might be banned if adequate safety precautions are not employed to prevent transmission of infections, such as Creutzfeld-Jakob disease (CJD). Regulatory agencies in other countries, such as the Japanese Ministry of Health, have gone even further by banning the use of cadaverous dura mater in brain surgery. Moreover, the World Health Organization (WHO) has recommended banning the use of cadaverous dura mater in brain surgery because of the risk of CJD transmission.
Dural substitutes comprising gold, silver, platinum, nickel, steel or gelatin have been researched; however, they have been found unacceptable for a variety of reasons, including high rigidity, poor incorporation, fibrosis, low resistance to infection and excessive foreign body response or regenerative processes. See, e.g., the references listed in the attached Bibliography.
Numerous studies have evaluated the safety and effectiveness of xenografts using non-human tissues as dural substitutes. Although non-human tissues are more readily harvested and mass-marketed than human tissues, they have not performed ideally as human dural substitutes.
Intact bovine pericardium tissue implants, while perhaps the most popular dural substitute in the U.S. at present, may transmit bovine spongiform encephalopathy (BSE). Intact tissues can cause excessive fibrosis and encapsulation, possibly resulting in the development of hemorrhagic complications, such as the formation of subdural hematomas and even death. Xenografting with porcine biomembrane has been shown to result in severe adhesions when infection occurred in animal studies, and xenografting with certain collagen laminates or collagen films has been shown to result in a severe inflammatory response comprising fibrosis, neomembrane formation and meningeocerebral adhesions. See Bang-Zong et al., "Study and clinical application of a porcine biomembrane for the repair of dural defects," 69 J. Neurosurg. 707 (1988); Kline, "Dural replacement with resorbable collagen," 91 Arch. Surg. 924 (1965); Jannetta et al., "Formaldehyde-treated, regenerated collagen film and film-laminate as a substitute for dura mater," 16 Surg. Forum 435 (1965); and Lee et al., "Experimental evaluation of silicone-coated Dacron and collagen fabric-film laminate as dural substitutes," 27 Neurosurg. 558 (1967).
A physiologically compatible dural substitute that does not create adhesions is particularly important when there is a need for repeated surgical treatment. In treating brain cancer, for example, cancers can recur, requiring repeated opening and closing of the dura mater to gain access to the recurring cancer and/or even repeated removal of cancerous sections of the dura mater. Patient outcomes could be improved by repairing the damaged dural tissue with a physiologically compatible dural substitute that does not create life-threatening adhesions. Moreover, doctors would be more willing to surgically intervene where indicated if the likelihood of creating adhesions were reduced.
Despite the previously reported problems with collagen xenografts, the inventors continued to work with collagen as a dural substitute. In 1993 and 1995, Narotam et al. (groups including some of the present inventors) reported that a collagen sponge showed promise as a dural substitute. See Narotam et al., "Experimental evaluation of collage sponge as a dural graft," 7 British J. Neurosurg. 635 (1993), and Narotam et al., "A clinicopathological study of collagen sponge as a dural graft in neurosurgery," 82 J. Neurosurg. 406 (1995). Although the collagen sponge disclosed in these papers appeared to effectively function as a dural substitute, there were significant safety issues still to be recognized and resolved.
The collagen sponge used (i.e., Bicol.RTM.) was bovine in origin and, despite its prior use as a temporary protective material on the brain surface beneath retractors, the collagen was not sufficiently decontaminated so as to preclude the possibility of causing a xenogenic infection when permanently implanted. Contrary to the knowledge and teachings of the 1995 article at page 410, right column, it is now known that the collagen sponge disclosed in the Narotam et al. articles poses a health hazard due to the possibility of infectious agents (e.g., prions and viruses) surviving the manufacturing process. The lack of significant chemical processing does not provide a suitable safety margin for the inactivation of viral or prion contaminants and therefore cannot adequately prevent, or reduce the likelihood of, infecting dural substitute recipients.
Thus, there has been a need for a mass-marketable collagen-based dural substitute that would be physiologically compatible (i.e., non-inflammatory, non-adhesion inducing, etc.), sufficiently noninfectious (i.e., decontaminated, etc.) to prevent the transmission of viruses and prions to dural substitute recipients, pliable, available in a variety of sizes, high in tensile strength, inert, optionally capable of forming a water-tight seal, and optionally suturable.
All references cited herein, including prior patent applications, are incorporated herein by reference in their entireties.